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Identifizierung und Charakterisierung zerebrovaskulärer Veränderungen nach Schädel-Hirn Trauma und ihre Bedeutung für die Entwicklung neuer Therapien
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DNA origami biosensors with single-molecule FRET readout: particle size characterization, vesicle detection and cargo transfer
Get PDFThe interaction of slug and actin in the DNA double-strand break repair and validation of AI designed potential actin binding compounds for drug discovery
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Glioblastoma cell-derived apelin has differential effects on myeloid cell migration
Get PDFDas Glioblastom (GBM) stellt den häufigsten malignen Hirntumor dar und betrifft pro Jahr in Europa etwa sechs von 100.000 Erwachsenen. Aggressive Interventionen zur Behandlung des Tumors umfassen die Chirurgie, Chemo- und Radiotherapie. Dennoch ist die Ein-Jahres-Überlebensrate mit 20% gering. GBMs charakterisieren sich durch sehr invasives Wachstum mit ausgeprägter Vaskularisation. Die Tumormasse besteht neben Tumorzellen auch aus Immunzellen. Diese tragen zur Bildung eines lokalen Milieus bei, das von den Tumorzellen für deren Wachstum und zur Infiltration anderer Hirnregionen genutzt wird. Tumorassoziierte Mikroglia und Makrophagen (TAM) repräsentieren bis zu 50% dieser Nicht-Tumorzellen in der Mikroumgebung von GBM, weshalb sie ein mögliches Ziel für zukünftige Therapien darstellen. Im GBM Mausmodell fand unsere Arbeitsgruppe unter der Leitung von Dr. Roland Kälin Hinweise auf eine signifikant erniedrigte TAM-Dichte im Umfeld von Gliomen deren APLN-Expression ausgeschaltet worden war. Hieraus resultierte die Hypothese, der Apelin-Apelinrezeptor (APLN/APLNR)-Signalweg könnte für die Rekrutierung myeloider Zellen durch GBM von Bedeutung sein.
In dieser Doktorarbeit wird der APLN/APLNR-Signalweg im Kontext der Interaktion von GBM und TAM untersucht. Ich zeige eine direkte Korrelation zwischen starker Expression von APLN in GBM und einer entsprechend erhöhten Dichte von TAM in der Mikroumgebung des Tumors auf. Zudem demonstriere ich, dass APLNR sowohl von BV2 Mikroglia als auch von J774 Makrophagen exprimiert wird. Eine immunologische Stimulation dieser Zellen mit Lipopolysaccharid (LPS) – zur Simulation einer Entzündungsantwort – resultiert in einer niedrigeren Expression des Rezeptorgens. Der APLN/APLNR-Signalweg scheint im Rahmen dieser Entzündungsantwort daher keine besondere Bedeutung zu haben.
Ich zeige auch, dass isoliertes Apelin-13 Peptid zwar die Migration von Mikroglia signifikant erhöht, jedoch auf die Mobilisation von Makrophagen keine größere
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Auswirkung hat. Für eine bessere Simulation der in vivo Situation verwende ich statt isoliertem Apelin-13 den Zellüberstand von kultivierten Gliomzellen. Ich vergleiche Medium von APLN-Wildtyp-Gliomzellen (WT) mit Medium von APLN-knockdown- Zellen (KD). Hierbei zeigen Mikroglia im Gegensatz zu Makrophagen ein überwiegend verändertes Wanderungsverhalten. Hohe APLN-Expression des Tumors führt zu einer chemo-attraktiven Wirkung auf BV2 Zellen. Daher vermute ich, dass verschiedene GBM Zellen unterschiedliche Signalwege zur Rekrutierung von Mikroglia nutzen – der APLN/APLNR-Signalweg wäre insofern vor allem für Tumore mit hoher APLN-Expression von Bedeutung. Für Makrophagen konnte ich keinen direkten Einfluss von Apelin auf deren Wanderungsverhalten zeigen.
Im Kontext von GBM wirkt APLN unterschiedlich auf Mikroglia und Makrophagen. Verschiedene GBM Zellen und deren APLN Expression scheinen das Verhalten von TAM auf unterschiedliche Weise zu beeinflussen. Es werden weitere Studien nötig sein, um die genaue Bedeutung des APLN/APLNR-Signalweges für die Rekrutierung vom TAM durch GBM offenzulegen. Für einige GBM Zellen scheint er jedoch von entscheidender Relevanz zu sein, womit er auch ein potenzielles Ziel zukünftiger Therapieansätze darstellt.
Werden Mikroglia und Makrophagen dem Kulturmedium verschiedener GBM Zellen ausgesetzt, so zeigt Mikroglia eine geringere Mobilität und Makrophagen eine gesteigerte. Immunhistologisch kann außerdem eine direkte Korrelation von APLN- Expression der GBM-Zellen und der Dichte an TAM im Gehirn gezeigt werden. Gemeinsam führen die Beobachtungen zu der Vermutung, dass Makrophagen im unmittelbaren Umfeld der Gliome die vorherrschenden myeloiden Zellen sind. Um dies jedoch ganz schlüssig zu beweisen, sind weitere Experimente mit einer immunhistologischen Differenzierung zwischen Mikroglia und Makrophagen notwendig.Glioblastoma (GBM) is the most common malignant brain tumor affecting approximately six people every 100.000 adults in Europe every year. Aggressive interventions like surgery, chemo- and radiotherapy have been established to treat the tumor, nevertheless the one-year survival rate is only 20%. GBMs are characterized as very invasive tumors with abundant vascularization. Their microenvironment was shown to include immune cells. These cells create a local milieu, which is used by neoplastic cells to grow and infiltrate other brain regions. Tumor-associated microglia and macrophages (TAM) represent up to 50% of these non-tumor cells in the microenvironment of GBM and therefore represent an interesting target for future therapies. In GBM mouse models our group – led by Dr. Roland Kälin – found a significant reduction of TAM density when APLN expression was knocked out in GBM cells. We considered apelin-apelin receptor (APLN/APLNR)-signaling might be part of GBM myeloid cell recruitment.
In this study I investigated the role of APLN/APLNR-signaling in the context of GBM cell interaction with TAM. I found a direct correlation of APLN expression levels and the density of TAM in the microenvironment of GBM. Furthermore, I showed APLNR to be expressed in BV2 microglia and J774 macrophages. Immunological stimulation of these cells with lipopolysaccharide (LPS) to simulate an inflammatory reaction resulted in a lower expression of the receptor gene. I considered APLN/APLNR- signaling to have a low relevance in the context of a typical inflammatory response.
I demonstrated that the apelin-13 peptide is chemoattractive for microglia but not for macrophages. To improve the simulation of the in vivo situation, I used glioma supernatant instead of recombinant apelin-13. Under these conditions I compared APLN wildtype (WT) and knockdown (KD) GBM cells. GBM-derived apelin affected migration of microglia stronger than migration of macrophages. I considered that GBM use various pathways – amongst them APLN/APLNR-signaling – to attract microglia towards the tumor. Microglia is attracted especially by strong APLN
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expressing GBM. For macrophages I could not show a significant influence of apelin on cell migration.
In the context of GBM, APLN acts in different ways on microglia and macrophages. Different GBM subtypes and their individual APLN expression levels have distinct effects on TAM. Further studies are required to fully disclose the role of APLN/APLNR-signaling in TAM recruitment of GBM. Nevertheless, APLN/APLNR- signaling seems to be a relevant pathway in this process for some glioma cells and therefore represents a potential therapeutic target in the future.
When microglia and macrophages are exposed to different GBM-conditioned medium, microglia show reduced mobility and macrophages increased mobility. In addition, a direct correlation between APLN expression of GBM cells and the density of TAM in the brain can be shown immunohistologically. Together, the observations suggest that macrophages are the predominant myeloid cells in the immediate vicinity of gliomas. However, to prove this, further experiments with an immunohistological differentiation between microglia and macrophages are necessary
How do social work students navigate professional practice situations?
Get PDFProfessional practice in social work is primarily considered as the capacity to pursue scientifically informed, method- and value-based interventions under conditions of complexity, paradoxes and uncertainties inherent in social work. As a nexus connecting knowledge and competence, professional practice aims at ensuring comprehensive examination, contextualisation, and interpretation of social problems of individuals or communities in a collaborative, solution-oriented approach. An essential target of social work education and training is therefore to thoroughly qualify students for professional practice. In order to equip students for the demanding practice of social work, universities have developed comprehensive curricula covering both, scientific knowledge, as well as practical skills. Nevertheless, there is little evidence about how social work students implement their theoretically acquired knowledge in the context of professional practice and how they approach complex and unpredictable situations of social work practice.
This dissertation aims at closing this gap by investigating professional practices of social work students. The overall aim of this explorative research is to analyse and conceptualise the scope of students’ approaches and strategies for professional practice in-depth, as well as to identify possible influential factors on their actions. Research that strives to understand student professional practice strategies also attempts to improve and foster professional development and thus, enhancing quality of teaching by proposing suggestions for improving classroom quality. By providing findings from two empirical studies, this dissertation aims at contributing to social work education. The two consecutive empirical studies of this thesis were conducted applying the grounded theory methodology. Subsequently, to address the research aims to the fullest extent possible, a qualitative-exploratory approach to research was used. When pursuing to assess students’ professional practice with a high level of authenticity, a realistic portrayal of social work practice was crucial. Therefore, a simulation involving a trained actress standardised client was developed as the research design’s superstructure. By modelling an initial assessment process, the students were encouraged to step into the role of a social worker and to interact professionally with an overstrained client. In total, 25 social work students (bachelor’s level), from four different universities across Germany participated voluntarily.
In the first study, the students’ professional practice was observed directly, based on non-participatory ethnographic observation and the examination of the video-taped simulations. Building upon the findings of this first study, the students’ reflections about their professional practice were placed at the core of the second study. This was accomplished through individual problem-centred interviews conducted after the simulation experience. More than 550 minutes of transcribed video and 650 minutes of interview material were analysed by using grounded theory’s systematic methods of open, axial and selective coding.
As a result of this investigation, two conceptual models were developed. These models detail action patterns, strategies, challenges, and influential aspects of the students’ professional practice. Evidence provided by both studies reveal the complexity of learning professional practice in social work. The findings highlight challenges encountered by students in performing the professional role of a social worker, building and maintaining a professional relationship with the client, and dealing with the assessment process in general. Misunderstanding the demands of the professional situation results in adopting alternative strategies, such as recourse to day-to-day knowledge, individual reflection criteria and evasive actions. Furthermore, there is evidence that the students’ prior experiences, whether professional or personal, may influence their professional practice.
Altogether, the results highlight substantial difficulties that the students face in terms of their capacity to engage in scientifically informed, method- and value- based activities under dynamic and unpredictable conditions of social work practice. Both studies strongly suggest that students should be given greater learning support in order to engage in the challenging practice of social work. Beyond this, the findings emphasise the relevance of providing students with opportunities to reflect on personal beliefs as well as prior experiences and, about how these may be influencing their professional practice.
Considering all this, it is reasonable to conclude that students need access to more authentic, realistic exercises with individual feedback to systematically develop their capacities for professional practice in social work. Providing simulations relating to particular practice situations of social work involving standardised clients seems to be a promising approach for social work education and the professional development of future social workers
